This invention relates to the fields of organic synthesis and organometallic chemistry. In particular, this invention relates to methods for the preparation of organic compounds through the sequential addition of substituent groups to a substrate molecule without isolation of intermediates.
The utility of organocopper complexes as reactive intermediates in a variety of synthetic reactions has been well known for decades. Particularly important reactions utilizing organocopper complexes in the formation of carbon-to-carbon bonds include addition reactions (such as 1,4-conjugate additions and carbocupration reactions) and substitution reactions (such as, for example, the displacement of halides, tosylates or mesylates and ring opening of epoxides). In such reactions, the organocopper complex formally serves as the source of a suitable carbanion for introduction into a target molecule by addition or displacement.
Early work in the field of organocopper chemistry involved treatment of either catalytic or stoichiometric quantities of a copper(I) halide with a Grignard (RMgX) or organolithium (RLi) reagent. The resultant products are either neutral organocopper reagents RCu(I) or copper(I) monoanionic salts R.sub.2 CuM (M.dbd.Li or MgX), commonly referred to as lower order or Gilman reagents. Copper(I) cyanide is also an excellent precursor for the direct formation of lower order cyanocuprates RCu(CN)Li upon treatment with an equivalent of an organolithium. It is believed that the strength of the Cu-CN linkage accounts for the direct cuprate formation with one equivalent of the organolithium, rather than the metathesis that occurs with copper(I) halides to produce an equivalent of LiX.
While such lower order complexes have some direct synthetic applications, it has further been determined that reagents of this type can be composed of different ligands (i.e., R.dbd.R'). In other words, rather than forming a complex of the formula R.sub.2 CuLi from two equivalents of the same RLi, different organolithium compounds can be used to provide a complex of the formula R.sub.T R.sub.R CuLi. In this manner, it is possible to conserve potentially valuable R.sub.T Li. Successful exploitation of such complexes comprising two different ligands is based on the ability to control the selectivity of transfer of the desired ligand R.sub.T rather than the residual (or "dummy") group R.sub.R from copper to electrophilic carbon.
A particularly significant advance in the field of organocopper complexes has been the development of so-called "higher order" cuprates. For example, the admixture of two equivalents of RLi (or one equivalent each of R.sub.T Li and R.sub.R Li) with copper(I) cyanide proceeds to the formation of a copper(I) dianionic complex or higher order cyanocuprate, R.sub.2 Cu(CN)Li.sub.2. The cyano ligand, with its .pi.-acidic nature, is believed to enable the copper to accept a third negatively-charged ligand in ethereal solvents (e.g., Et.sub. O and THF). Such higher order complexes, particularly those derived from two different organolithium compounds, have been successfully exploited as highly selective and efficient means of making key carbon-to-carbon bonds.
The use of cuprates in 1,4-conjugate addition reactions for introduction of unsaturated carbanions is especially attractive due to the complete control of double bond geometry in the reaction scheme. This is of particular significance, for example, in the synthesis of various prostaglandins via conjugate addition of an alkenyl moiety to the unsaturated ketone functionality of a substituted cyclopentenone.
The preparation of reactive vinylic organocuprate reagents has involved a limited number of typical reaction pathways. For transfer of a particular alkenyl side chain to a target molecule, vinylic halides (usually, the bromides or iodides) and vinylic stannanes have typically been employed as a precursor molecule. These precursor molecules are generally prepared from the corresponding acetylene and converted to the reactive copper reagents for use as synthetic intermediates.
Campbell et al. U.S. Pat. No. 4,777,275, the entire disclosure of which is hereby incorporated by reference, describes a process for preparing a higher order copper complex in which a ligand (designated R.sub.t) which is desired in a subsequent synthetic organic reaction to form a new carbon-to-carbon bond is transferred in situ from a stannane compound to a first higher order copper complex to form a second higher order copper complex including the ligand. Of course, to employ this method it is first necessary to prepare specific vinyl stannanes by art recognized techniques. Such techniques generally call for the reaction of a suitable acetylene with, e.g., a trialkyl tin hydride. Unfortunately, the stannanes are generally quite toxic and do not react to afford only the desired regio- and stereoisomer; rather, a mixture of vinylstannanes which cannot be easily separated is usually obtained. Therefore, it would be advantageous to avoid such intermediates entirely if possible.
Preparation of suitable cuprate complexes from the corresponding halides is also problematic, particularly in the case of alkenylhalides. Formation of the desired cuprates is generally effected from the corresponding alkenyllithium compounds, which in turn are prepared by metal-halogen exchange (typically using two equivalents of highly pyrophoric and expensive -t-butyllithium) with the corresponding alkenylhalides or reaction of the halides with lithium metal. Preparation of the organolithium precursors via this latter method is typically tedious, and may result in low yields. Moreover, in the case of the alkenyl compounds, there may be some loss of double-bond stereochemistry.
According to Grudzinskas et al. U.S. Pat. No. 4,415,501, the disclosure of which is also hereby incorporated by reference, some of the potentially problematic issues associated with the chemistry involved in the formation of vinylic cuprate complexes are avoided by utilizing an alternative class of reagents. A class of alkenylzirconium reagents are described, which may be employed directly in various conjugate addition reactions. These alkenylzirconium reagents are prepared by reaction of the corresponding protected alkynol with dicyclopentadienyl zirconium chlorohydride; the latter is typically generated in situ by the reduction of dicyclopentadienyl zirconium dichloride in solution under an inert atmosphere. The thus-prepared alkenylzirconium reagents are described as moisture sensitive, and thus it is suggested that they are best prepared just prior to use. Reaction of the alkenylzirconium reagents with the target molecule for a conjugate addition is effected in the presence of a catalytic amount of a reduced nickel catalyst.
While the method of U.S. Pat. No. 4,415,501 obviates some of the potential problems associated with the formation of the reactive cuprates, it does so at the cost of yield and purity of the resultant products, as is immediately apparent from a review of Table II of the reference. Indeed, while the products of hydrozirconation reactions may be utilized in selected coupling reactions to form carbon-to-carbon bonds, there is no general established method for directly transferring these ligands to alpha, beta unsaturated ketones in a conjugate (i.e., 1,4-) sense. Therefore, the reference method using organozirconium compounds directly as reagents is limited in applicability and clearly unacceptable for the preparation of most products, in particular from relatively expensive optically-active intermediates, on a commercial scale.
Hydrozirconation of alkenes by zirconocene chloride hydride, followed by addition of one equivalent of enone and catalytic amounts of Cu(I) or Cu(II) salts (such as CuBr, CuI and CuCN) has been reported to lead to the corresponding 1,4-addition products in moderate to high yield [Wipf, P. et al., J. Org. Chem. 56, 6494 (1991)]. This method was demonstrated only in very simple systems (i.e., not in .alpha.- or .beta.,.beta.-disubstituted cases) and only with alkylzirconocenes.
Lipshutz et al. U.S. Pat. No. 5,072,010, the entire disclosure of which is hereby incorporated by reference, discloses a method whereby higher order cuprate complexes of the type described in, e.g., Campbell et al. U.S. Pat. No. 4,785,124, are prepared by means of a transmetalation from a corresponding zirconocene intermediate. This process is particularly valuable with respect to the introduction of vinylic side chains such as are present at the 3-position on the cyclopentanone ring in prostaglandins (commonly referred to as the .beta. side chain), as it is possible in accordance with the present invention to proceed directly from the acetylenic precursor 1 via the reactive cuprate to the desired final product 2 in a one-pot operation without isolation of intermediates and in high yields (Scheme 1). ##STR1## Thus, the problems associated with the preparation of the corresponding vinyl halide 3 or stannane 4 so as to provide an alkenyllithium 5 (Scheme 2) are avoided entirely. ##STR2##
While the method disclosed in U.S. Pat. No. 5,072,010 is particularly attractive relative to the heretofore known approaches for preparation of organocuprates, the intermediate enolate formed using a cuprate as ligand source for a 1,4-conjugate addition has not been found to be susceptible to electrophilic trapping. As a consequence, preparation of a prostaglandin product as described in U.S. Pat. No. 5,072,010 requires that the side chain in the 2-position on the cyclopentanone ring (i.e., the upper or .alpha. side-chain) of the target prostaglandin be already in place in the cyclopentenone precursor.
It would be advantageous to provide a synthetic method in which 1,4-addition of, e.g., a vinylic cuprate to an enone would lead to an intermediate capable of subsequent trapping by an electrophile at the 2-position. As illustrated in Scheme 3, this would provide a method whereby introduction of side chains at both the 2- and 3- positions on the cyclopentanone ring of a target prostaglandin (i.e., the .alpha. and .beta. sidechains, respectively) could be accomplished in a single reaction sequence. As indicated, in such a sequence reaction of the cyclopentenone 7 with, e.g., a cuprate provides an intermediate 8, which in turn reacts with an electrophile (E.sup.+) to provide the desired prostaglandin product 9. ##STR3##
Several approaches have heretofore been proposed for a "three-component coupling" reaction of the type as generally illustrated in Scheme 3. One approach involves in situ formation of an organocopper reagent from equimolar amounts of copper(I) iodide and a vinyl lithium, with 2-3 equivalents of tributylphosphine, to effect a conjugate addition of the .beta. side chain to the enone. As direct alkylative trapping of the resulting enone could not be attained in this form, triphenyltin chloride and HMPA are added; reaction then occurs with an .alpha. side-chain Z-allylic iodide [Suzuki, M. et al., J. Am. Chem. Soc. 107, 3348 (1985); Suzuki, M. et al., J. Am. Chem. Soc. 110, 4718 (1988)]. An alternative approach is through conjugate addition of the .beta. side-chain in the form of a mixed zincate, (vinyl)Me.sub.2 ZnLi, to the enone 7 followed by enolate trapping using an .alpha. side-chain electrophile [Suzuki, M et al., Tetrahedron 46:4809-22 (1990); Noyori, R. and Suzuki, M., Chemtracts--Organic Chemistry, pp. 173-197 (May-June 1990)]. Pursuant to this method, an equimolar mixture of dimethylzinc and the .beta. side-chain vinyllithium (forming the mixed zincate) is treated sequentially with the cyclopentenone 7 and an .alpha. side-chain propargylic iodide (in the presence of some HMPA) to form the desired fully-substituted product (Scheme 4). ##STR4## The .beta. side-chain vinylic lithium is generated either by transmetalation between a tributyltin derivative and n-butyllithium, or by halogen-metal exchange between the corresponding vinylic iodide and t-butyllithium [Noyori, supra, at pp. 176-177]. Thus, in order to prepare the .beta. side-chain precursor for use in the "three-component coupling" method developed by Noyori et al. from the corresponding acetylene, a plurality of steps (including purification and isolation of intermediates) is necessary (Scheme 5). ##STR5## Pursuant to either approach for preparation of the .beta. side-chain vinyllithium reagent 5, one thus confronts the same problems previously encountered with prior art routes for preparation of cuprates from the corresponding iodides or stannates (Scheme 2, supra).
The use of lithium triorganozincates in 1,4-conjugate addition reactions has been known for some time [Isobe, M. et al., Chemistry Letters, pp. 679-682 (1977)]. It has been recognized, however, that these reagents are not very reactive in 1,4-addition reactions; in many cases, either the desired addition reaction does not take place at all, or the yield of product is very poor [Tuckmantel, W. et al., Chem. Ber. 119:1581-93 (1986)].
It is an object of the present invention to provide a method for effecting an improved three-component coupling reaction, comprising a 1,4-conjugate addition to an enone followed by electrophilic trapping of the intermediate enolate, which does not suffer from the drawbacks attendant to the heretofore known methods.